The Strong Link between Circadian Cycle Dysfunctions and Bipolar Disorder

Objective
Bipolar disorder is recognised as a complex, heritable disorder that has both genetic and environmental susceptibility factors. Among these factors, there is increasing evidence that abnormalities of circadian rhythms may distinguish BD cases from healthy control subjects.
During this essay, I intend to outline how abnormal circadian rhythms are ever-present in Bipolar Disorder. I aim to do this by presenting strong points ascertaining that there is an evident pathophysiological relationship between circadian rhythm dysfunction and BD. The elements of the circadian cycle that I will investigate are melatonin, light, cortisol and clock genes. 
What is Bipolar Disorder (BD)?
Bipolar Disorder is defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a group of brain disorders that cause extreme fluctuation in a person’s mood, energy and ability to function. BD includes three different disorders. Bipolar I disorder is a manic-depressive disorder which can exist with and without psychotic episodes. Bipolar II disorder is one of both manic and depressive episodes that alternate and are typically less severe, they do not inhibit function. Cyclothymic disorder is a cyclic disorder that causes brief episodes of hypomania and depression. Sleep disturbance is listed as a symptom of each; reduced need for sleep is a symptom of manic and hypomanic episodes; and insomnia or hypersomnia are listed as symptoms of major depressive episodes.
Between mood episodes, residual symptoms remain. These residual symptoms come in the form of sleep alterations, circadian cycle disturbances, emotional deregulation, cognitive impairment and increased risk for comorbidities (Leboyer and Kupfer, 2010 ).
How many people are affected by Bipolar Disorder and when?
These are the statistics according to the World Mental Health Survey on the total lifetime prevalence of BD: Type I BD is 0.6%, type II BD is 0.4% and cyclothymic BD is 1.4%. This yields a combined estimated prevalence for the BD spectrum of 2.4% worldwide (Merikangas et al., 2011). The average age of onset is between the age of 17 and 27 and this does not differ between both sexes (Gelder et al., 2000).

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What is a circadian cycle?
There are several rhythms that instruct our bodies. When these rhythms have the approximate duration of 24 hours, they are deemed circadian – “circa diem” – about a day. These time measuring devices that most light-sensitive organisms (from cyanobacteria to humans) are equipped with, allow them to anticipate daytime. Thus, they are able to organise their physiology and behaviour in a proactive rather than a responsive manner. Circadian cycles manifest themselves in the temporal organisation of physiological, cellular, neural, biochemical and behavioural processes (Dibner et al., 2010 ). For there to be an alignment between the internal time and geophysical time, our body has to pick up environmental cues known as zeitgebers (time giver) – these come in the form of temperature, food intake and the day/night or light/dark cycle. The photoperiod is the most dominant and important zeitgeber.
How does the circadian cycle work?
In mammals, the circadian timing system is composed of as many clocks as there are cells meaning virtually all cells in the body are autonomous circadian oscillators. The light information has to reach all the cells and thus has to be processed by a central clock. This central clock is located in a pair of small nuclei in the anterior region of the hypothalamus, the suprachiasmatic nuclei (SCN) (Foster and Hankins, 2007). The SCN processes information and then delivers it to various other clocks in the brain located in other hypothalamic nuclei, thalamus, amygdala and habenula. This synchronises all individual endogenous rhythms. The transmission of circadian information is done by means of metabolites and hormones and also via direct neural control involving the neuroendocrine system and autonomic nervous system (Dibner et al., 2010).

Figure 2  Circadian oscillators in the mammalian brain.
Blue = semiautonomous oscillators
Red  = self-sustained circadian oscillators
Green = slave oscillators
AMY, amygdala; ARC, arcuate nucleus; BNST, bed nucleus of the stria terminalis; CB, cerebellum; CX, cortex; DG, dentate gyrus; DMH, dorsomedial hypothalamus; DRN, dorsal raphe nucleus; HB, habenula; Hip, hippocampus; LH, lateral hypothalamus; ME, median eminence; MRN, median raphe nucleus; NAc, nucleus accumbens; NTS, nucleus of the solitary tract; OB, olfactory bulb; OVLT, vascular organ of the lamina terminalis; Pi, piriform cortex; Pin, pineal gland; Pit, pituitary gland; PVN, paraventricular nucleus of the hypothalamus; PVT, paraventricular nucleus of the thalamus; Ret, retina; RVLM, rostral ventrolateral medulla; SCN, suprachiasmatic nuclei; SON, supraoptic nucleus; VLPO, ventrolateral preoptic area; VTA, ventral tegmental area.
What role do melatonin abnormalities play in Bipolar Disorder?
Melatonin is one of the circadian information pathways. Melatonin is a hormone mainly produced in the pineal gland which is released into the cerebrospinal fluid and into circulation targeting various tissues. Melatonin’s production is suppressed by light, thus presenting a circadian variation. Its levels gradually increase overnight with its peak level occurring in the middle of the night. Melatonin levels then gradually decrease towards the beginning of the day (Kalsbeek et al., 2006). Melatonin has circannual variation whereby it increases in proportion to the duration of the night. Speaking at a molecular level, melatonin acts on the expression of clock genes in the pars tuberalis of the pituitary and influences the SCN directly by binding to its melatonin receptor 1 (MT1) and 2 (MT2). It inhibits the electrical and metabolic activities of SCN neurons, hence, altering the phase and amplitude of circadian cycles.
BD individuals may show changes in the levels and phases of melatonin secretion. Studies have found an increase in night-time melatonin peak (Lewy, 2009) and an increase of its levels in general during episodes of mania (Novakova et al., 2014). In contrast to these finding, another study carried out by Robilard et al., 2013 compared unipolar depression with BD. They concluded that BD individuals had significantly lower levels and later onset of melatonin secretion than those with unipolar depression. Another study carried out by Dallaspezia and Benedetti, 2009 concluded that there is a delayed peak melatonin time in euthymic (stable state i.e. neither manic/hypomanic nor depressed) BD patients. Another concept to consider is that changes in melatonin levels are an inherent feature of BD as opposed to being accepted as merely a stage in the disease. A study that backs this up is one that found lower levels of melatonin in euthymic patients, depression episodes and even mania when compared with healthy controls (Nurnberger et al., 2000).
As melatonin is a strong endogenous synchronizer whose production is influenced by light, it makes sense that the influence of light on BD individuals is investigated.
What role does light sensitivity play in Bipolar Disorder?
As outlined previously, our circadian systems are particularly sensitive to the zeitgeber light. A process known as entrainment keeps our system aligned with external time and allows it to shift as the balance of light and dark varies across the seasons and as we travel from one time zone to another. Several studies have suggested that BD is characterised by hypersensitivity to light. The production of melatonin is usually suppressed by light of 500 lux or greater (Lewy et al., 1980).
When BD patients were exposed to a light source during the night, a greater suppression of melatonin synthesis was noted in BD subjects as compared to healthy subjects (Lewy et al., 1985). Animal models have also been helpful in clarifying the relationship between light hypersensitivity and BD individuals. Timothy et al., 2018 aimed to characterize the circadian and light-associated behavioural features of the Na+/K+-ATPase α3 Myshkin mouse model of mania. Their study showed that, independent of clock gene alterations in the SCN, the animals presented with alterations of sleep patterns and circadian rhythms. These circadian alterations include an increase in the period and active phase duration of behavioural circadian rhythms along with an instability of these rhythms and increased phase-shifting/re-entrainment responses to light . This hypersensitivity to light was present during the manic, depressive and euthymic phase and thus it can be concluded as a trait that is not state-dependent. It is thus speculated to be a trait-marker or endophenotype (biological marker) of BD (Lewy et al., 1985).
How is cortisol a marker in circadian rhythms and what is its role in Bipolar Disorder?
Another SCN pathway part of the circadian cycle in mammals is the one that produces cortisol. Cortisol is the body’s main stress hormone. This pathway involves the hypothalamic-pituitary adrenal axis . It promotes the release of corticotropin-releasing hormone by the paraventricular nucleus, which stimulates the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. ACTH then enters the circulation and will stimulate the production of glucocorticoids in the cortex of the adrenal glands.
In a circadian rhythm, cortisol levels fluctuate daily reaching its zenith (high-point) after waking up and its nadir (low-point) in the night (Kalsbeek et al., 2006).  In addition to controlling the rhythm of cortisol production, SCN also modulates the sensitivity of the adrenal gland to the ACTH (Buijs et al., 2003), (Nader et al., 2010). Cortisol has an impact on peripheral clock in nearly all tissues and organs by adjusting the phase of the cycle under stressful situations. Because cortisol does not reach the SCN, its intrinsic circadian rhythm is kept regardless of the changes in the rest of the body. In this way, once the stress situation has been resolved, the SCN resynchronizes the peripheral clocks ( Nader et al., 2010 ).
Cortisol is also one of the most widely used markers of circadian cycles. Many individuals with BD show evidence of increased activity at several levels of the hypothalamic–pituitary–adrenal (HPA) axis during manic and depressive levels such as Linkowski et al., 1995, Cassidy et al., 1998 among many others. Linkowski et al., in 1994  studied BD patients experiencing a manic episode and they concluded that the BD patients showed higher cortisol levels at night and an early nadir compared to healthy controls. Another study also extended the evidence of hypersecretion of cortisol to depressive episodes ( Gallagher et al., 2007). However, the question lies in whether these abnormalities are limited to the episodes themselves or might they also be present before the onset of BD or later during periods of clinical remission. A recent study investigated the difference in daytime cortisol levels and cortisol levels in reaction to daily events between remitted BD individuals and a healthy control group. Their results showed that daily levels and reactivity to daily events were similar but that the BD individuals showed flatter diurnal slopes and larger cortisol fluctuations. Within the study, it was noted that patients with many previous episodes as opposed to patients with fewer previous episodes, had higher overall cortisol levels, reduced cortisol reactivity to negative daily events, and flatter diurnal slopes (Havermans et al., 2011). Evidence from challenge tests indicates persistent HPA dysfunction after clinical remission from BD episodes as demonstrated by Deshaur et al., 1999 when BD patients demonstrated intermittent cortisol non-suppression during monthly tests. In short, studies suggest that HPA axis dysregulation precedes, accompanies and follows bipolar episodes and thus may be a trait characteristic (Daban et al., 2005). It has been observed that there are therapeutic benefits by decreasing cortisol levels through the use of antagonists (Young, 2006). As cortisol (and melatonin) is controlled by clock genes, it makes sense that these are thoroughly investigated as markers in BD.
Can clock genes act as a predictor in Bipolar Disorder?
Another element of circadian rhythm markers are clock genes. Clock genes are what control the SCN and peripheral clocks by means of negative feedback loops involving transcription and translation of these genes. The main circuit includes the genes CLOCK –circadian locomotor output cycles kaput, and the brain and muscle ARNT-like gene-1 (BMAL1) that translate the CLOCK and BMAL1 proteins. These form a heterodimer that promotes the transcription of period genes (per1, per2 and per3) and cryptochromes genes (cry1 and cry2) during the day.
 With the development of molecular genetic techniques that allow cloning and characterisation of clock genes individually, we have the possibility to explore the molecular mechanisms behind the relationship between BD and circadian cycles. Polymorphisms in molecular clock genes not only show a great association with BD but also seem to have an effect on the response to treatment and symptomatology characteristics. The CLOCK gene has been widely investigated in patients with BD. Several studies have been conducted on a single nucleotide polymorphism (SNP) in the CLOCK gene. This particular polymorphism involves the substitution of the nucleotide thymine (T) for cytosine (C) at position 3111 of this gene – described as SNP T3111C. Some studies have revealed that patients with BD which have at least one copy of allele 3111C have an evening chronotype (Katzenberg et al., 1998, Benedetti et al., 2003, Benedetti et al., 2007, Lee et al., 2007). It is thus plausible to conclude that this polymorphism has a great influence on circadian rhythm abnormalities in BD patients.
The homozygous for this allele 3111C present several differences from the 3111T allele homozygous or heterozygous, in particular, show a doubling of the rate of recurrence of bipolar episodes (Benedetti et al., 2003). This polymorphism has also proven to result in an increased recurrence of insomnia in BD patients (Seretti et al., 2003). Another profound conclusion from a studied carried out by Benedetti et al., 2003 is that the homozygous for this allele 3111C present several differences from the 3111T allele homozygous or heterozygous, in particular, show a doubling of the rate of recurrence of bipolar episodes.
Moreover, it was demonstrated that mice with mutations in this gene displayed behaviours similar to that of mania – showing hyperactivity, decreased sleep, increased exploring activity and greater sensitivity to altered photoperiod (Roybal et al., 2007).
It can therefore be concluded that clock gene variations are indicators in BD with respect to recurrence and various other aspects of the disorder.
Conclusion
A great number of studies have outlined the strong link between circadian cycles and BD making it impossible to ignore this relationship. I have shown how the circadian system is  one of ubiquity in our body which heavily influences our bodies’ behaviour, physiology, cell biology, biochemistry, etc. and this makes it very hard to argue that it would not influence a condition like BD. This is evident as almost all symptoms of BD such as changes in mood, energy, sleep, appetite, ability to concentrate, among others, present a circadian variation. Likewise, an effective BD treatment generally involves the normalization of circadian function. Although there does not exactly lie a causal relationship between circadian rhythm dysfunction and BD, I believe I have outlined some strong factors which indicate that circadian cycle abnormalities play a crucial role in the pathophysiology of BD.
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